There is an urgent public need to develop effective pharmacotherapies for methamphetamine (meth) dependence. There are up to 57 million amphetamine users worldwide.1 Use of meth (rapidly metabolized to amphetamine) is up to 20 times more prevalent among men who have sex with men (MSM) than in the general U.S. population, and is a major contributor to the HIV epidemic.2-4 Meth use is independently associated with high-risk sexual behavior5-9 and HIV seroconversion.10-12 Effective meth treatments therefore will not only reduce meth use, they could also be important HIV prevention interventions by reducing meth-driven sexual risk. There are no FDA-approved pharmacologic treatments for meth dependence, a major gap in the field, because behavioral interventions alone have limited efficacy and would likely benefit from adjunctive pharmacologic treatments.13,14 In a recent double-blind, randomized controlled trial of modest size (n=60) and limited duration (12 weeks), we discovered that compared with placebo, oral mirtazapine, an antidepressant with serotonergic and dopaminergic properties, significantly reduced meth use as determined by reduction in urine positivity in the treatment arm (RR 0.57, 95% CI 0.35-0.93, p=.02).15 Sexual risk behaviors also declined significantly in the treatment arm compared to placebo. Mirtazapine decreased meth use despite low adherence: by medical event monitoring system (MEMS) caps, only 48.5% of daily doses were taken. All participants received a behavioral platform of weekly substance use counseling and monthly, brief clinician- delivered adherence counseling. We propose expanding upon these exciting results by determining mirtazapine's efficacy at both 12 and 24 weeks with daily adherence reminders added to the above trial's behavioral platform, and determining if efficacy is sustained up to 12 weeks after drug discontinuation. A sample size of 120 will ensure greater precision of results than the original trial. The primary specific aims of this study are: (1) To determine the efficacy of mirtazapine daily vs. placebo in reducing meth use and HIV sexual risk behaviors among actively- using meth-dependent MSM from 0-12 weeks of treatment. Participants in both arms will receive the behavioral platform of in-person weekly substance use and monthly brief adherence counseling, augmented by daily text messaging adherence reminders. (2) To determine if the efficacy of mirtazapine vs. placebo is sustained from 12-24 weeks on treatment, with both arms receiving the behavioral platform. (3) To determine if the efficacy of mirtazapine vs. placebo is sustained from 24-36 weeks, after discontinuation of medication or placebo and the behavioral platform at 24 weeks.